3, 17-bisoxygenated androst-4-en-9alpha-ols



3,17-BISOXYGENATED DRGST-4-EN-9 ct-OLS Raymond M. Dodson, Park Ridge, 10., assignor to G. i). Searle & (30., Chicago, 111., a corporation of Delaware No Drawing. Filed Dec. 22, 1959, Ser. No. 861,210

7 Claims. (Cl. 260-69145) wherein X is selected from the group consisting of carbonyl, B-hydroxymethylene, and B-(lower alkanoyl) oxymethylene radicals; and Y is selected from the group consisting of ,B-hydroxymethylene and p-(lower'alkanoyl) oxymethylene radicals. Lower alkanoyl radicals which X and Y can represent are exemplified by formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branchedchain isomers thereof, said groups being the acyl radicals of alkanoic acids containing fewer than 7 carbon atoms.

A starting material suitable for the manufacture of the compounds of this invention is 9a-hydroxyandrost-4-ene- 3,17-dione. Treatment of this diketone with a limited quantity of sodium borohydride and aqueous sodium hydroxide in methanol results in selective reduction of the l7-keto group, thus producing 9a,l7 8-dihydroxyandrost-4-en-3-one. When excess sodium borohydride is utilized in this reduction, a mixture of epimeric 3,9a,17-triols is obtained. Acylation of this epimeric mixture, suitably with a lower alkanoic acid anhydride in pyridine, affords the corresponding 3B,l7;3-di-(lower alkanoate). For example, treatment with acetic anhydride in pyridine yields 3,8,17p-diacetoxyandrost-4-en-9eol. Hydrolysis of these 35,17t3-di-(lower alkanoates), preferably with aqueous sodium hydroxide, produces the instant androst-4-ene-3{3,9u,17,8-triol. This triol can be oxidized with manganese dioxide in a suitable solvent to afford the aforementioned 9a,17/3-dihydroxyandrost-4-en- 3one.

When the instant 9a,l7B-dihydroxyandrost-4-en-3-one is subjected to acylating conditions, for example by reaction with a lower alkanoic acid anhydride in pyridine, the corresponding 17fi-(lower alkanoate) is obtained. As a specific example, by reaction with acetic anhydride in pyridine, l7B-acetoxy-9e-hydroxyandrest-4- en-3-one is produced.

When the aforementioned androst-4-ene-3B,9a,l7fltriol is treated with a limited quantity of an acylating agent, a mixture of the 3p-rnono-(lower alkanoate) and the l7B-mono-(1ower alkanoate) is obtained. These mono-(lower alkanoates) are separable by chromatography. For instance, reaction of this triol with acetic anhydride in pyridine results in 3(3-acetoxyandrost-4-ene- 90:,17B-di0l and l7p-acetoxyandrost-4-ene-3[3,9a-diol.

The compounds of this invention are useful as a result and one-quarter hours.

2,964,543 Patented Dec. 13, 1960 2 of their valuable pharmacological properties. They possess, for example, hormonal and anti-hormonal properties in consequence of their androgenic activity and their ability to inhibit the sodium-retaining activity of desoxyco-rticosterone acetate.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.). Quantities of materials are expressed in parts by weight except where otherwise noted.

Example 1 To a warm solution of 5 parts of 9a-hydroxy-androst- 4-ene-3,l7-dione in 32 parts of ethanol is added a solution of 2.5 parts of sodium borchydride in 30 parts of water and 24 parts of ethanol. The reaction mixture is allowed to stand at room temperature for one and onehalf hours, then treated with dilute acetic acid to destroy the excess borohydride. The solution is diluted with water and extracted with methylene chloride. The organic extract is washed with water, .dried'over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue is crystallized from benz- (me to yield crude androst-4-ene-3,9a',l7-triol; M.P. l63168. :;Y--. g1;

A mixture of 1.66 parts of the aforementionedi'crude triol, 5 parts of acetic anhydride, and 20 parts of pyridine is allowed to stand at room temperature for about one The solution is diluted with ice water and the resulting crystalline product collected by filtration. Recrystallization from aqueous acetone yields 36,l7B-diacetoxyandrost-4-en-9a-ol, M.P. 162-1645 [0c] =+4.0.

By substituting isovaleric anhydride and otherwise proceeding according to the herein-described processes, 3B,17,8-diisovaleryloxyandrost-4-en-9a-ol is obtained. Its infrared absorption spectrum possesses maxima at 2.9, 5.7. 5.8. and 6.0 microns.

Example 2 A mixture of 2.7 parts of 35,17B-diacetoxyandrost-4- en-9a-ol, 40 parts of methanol, and 50 parts of an aqueous solution containing 3 parts of sodium hydroxide is stirred at room temperature for one hour to achieve solution, then allowed to stand for 2 hours longer. The solution is neutralized with acetic acid, diluted with water, and extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate and evaporated to dryness. in vacuo to yield the crude product. Recrystallization from an acetone-cyclohexane solution results in pure androst-4- ene-3B,9e,17 3-triol, M.P. 177-179; [a] =+37.9.

Example 3 To a solution of one part of crude androst-4-ene- 3,9a,17-triol in 120 parts of benzene is added 10 parts of manganese dioxide, and the mixture is stirred at room temperature for 7 hours. The reaction mixture is filtered to remove the mixed manganese oxides and the filter cake washed successively with ethyl acetate and acetone. The filtrate and washings are combined and evaporated to dryness in vacuo. The residue is dissolved in 10% ethyl acetate-% benzene and adsorbed on a silica gel chromatographic column. Elution with 35% ethyl acetate-65% benzene followed by crystallization from acetone-cyclohexane afiords 9a,l7fl-dihydroxyandrost-4-en-3-one, M.P. 198-200"; [u] =+104 Example 4 To a stirred solution of 5 parts of 9a-hydroxyandrost-4- ene-3,l7-dione and one partof sodium hydroxide in 800 parts of methanol is added,- at;2-4;, a solution ofjone part of'sodium borohydride in 201partsofwater, reaction mixture is stirred at: Z4- for. one-hour, then neutralized with 10' parts of acetic acid. The'mixture:

is distilled to remove the methanol, then diluted with,

water; and the-resulting precipitate. is collected: by filtration, dissolved in ethyl acetate-80% benzene, and; adsorbedton silica gel. Elution-of-the column-withv 35% ethyl acetate-65%" benzene, followed by crystallization from acetone cyclohexaneyields 90:,17;8+dihydroxyan-,v drost-4'-en3'-one.- This product is identicalcwith that. described-in Example 3.

Example, 5

A,mixture oi 3 parts of, and rost-.4 en s-3,8, 9e,17 -diol, one part of acetic anhydride, and 10 parts of pyridine is allowed to; stand, at, room, temperature for. about 16 hours; then diluted with. water and extracted with methylene chloride. This organic extract is washed successively with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate, and evaporated to d ry,- ness in vacuo. A benzene solution of the residue is adsorbed on silica gel. The columnis washed with 10% The,

4 ethyl acetate in benzene. Successive elutions with 30% ethyl acetate in benzene result in 3fi-acetoxyandrost-4- ene-9a,175-diol and 17,8-acetoxyandrost-4-ene-3/8,9ot-diol, M.P. 214.5-216.5.

The substitution of an equivalent quantity of propionic anhydride in the process of this example results in 3 3- propionoxyandrost-4-ene-9a,17B diol and 17,8-propionoxy androst-4-ene-3B,9a-diol.

What is claimed" is: 1. Acompound of the structural, formula CH; CH

v r: r L 6 wherein X is selected from the group consisting of car honyl, B-hydroxymethylene, and fi-(lower alkanoynoxy methylene radicals; and Y is selected from the group consisting of ,B-hydroxymethylene and fi-lower alkanoyl)- oxymethylene radicals.

. 9a,17fi-dihydroxyandrost-4-en-3-one. l7B-acetoxy-9a-hydroxyandrost-4-en-3-one. 3B,17B-diacetoxyandrost-l-enfim-ol. Androst-4-ene-3;9,9a,l'7fl-triol. 3,8-acetoxyandrost 4-ene-9a,175-diol. 1713-acetoxyandrost-4-ene-3fi,9u diol.

immature Chinn et-aL: J. Org. Chem, vol. 24, No. 6, Iuue 19 59, pag

zen-p.61 2,514,31 

1. A COMPOUND OF THE STRUCTURAL FORMULA 